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Selection of Patients With Myelodysplastic Syndrome for Allogeneic Hematopoietic Stem Cell Transplantation
SOHO Supplement 2016
Selection of Patients With Myelodysplastic Syndrome for Allogeneic Hematopoietic Stem Cell Transplantation Asmita Mishra, Claudio Anasetti Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for patients with myelodysplastic syndrome (MDS). Because MDS predominantly affects an older population, age-associated comorbidities can preclude patients from cure. HSCT is associated with the risk of morbidity and mortality; however, with safer conditioning regimens and improved supportive care, eligible patients with an appropriately matched donor can receive this therapy without exclusion by older age alone. We discuss the role of improved MDS prognostic scoring systems and molecular testing for selection for HSCT, and review the pre-HSCT tolerability assessment required for this advanced aged population. Clinical Lymphoma, Myeloma & Leukemia, Vol. 16, No. S1, S49-52 ª 2016 Elsevier Inc. All rights reserved. Keywords: HSCT, MDS, Myelodysplasia, Somatic mutations, Transplant Tolerability
Introduction Myelodysplastic syndrome (MDS) encompasses a heterogeneous spectrum of malignancies characterized by ineffective hematopoiesis and morphologic dysplasia, with a predisposition toward leukemic transformation.1 Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative therapy currently available for MDS. MDS predominantly affects older persons; thus, until recently, many patients were precluded from this curative treatment option because of age alone. However, with the development of safer transplant conditioning regimens and supportive care measures, transplantation can now be offered to a wider patient population. Thus, the HSCT volumes for MDS have increased by 3.7-fold during the past decade in the United States, and MDS is currently the second most common indication for transplantation.2,3 Comprehensive patient evaluation for transplant tolerability remains an area of active investigation, given the potential for treatment-related complications to offset the benefits of transplantation. Furthermore, with the advent of newer models with improved prognostic capacity, the indications for transplantation need to be refined and updated. Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center, Tampa, FL Submitted: Feb 9, 2016; Accepted: Feb 9, 2016 Address for correspondence: Asmita Mishra, MD, Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612 E-mail contact: asmita.mishra@moffitt.org
2152-2650/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2016.02.023
Transplantation for MDS: Comparison With Non-HSCT Therapy For patients with advanced MDS who are eligible for transplantation, the superiority of HSCT compared with non-HSCT therapies has been reported in both retrospective and prospective analyses. Platzbecker et al4 compared DNA-hypomethylating therapy (n ¼ 75) to allogeneic HSCT (n ¼ 103), using a donor versus no donor retrospective analysis of patients with MDS aged 60 to 70 years. Those patients who did not have a search for a donor because of age 60 years or those with an unsuccessful donor search were used as the control arm. The estimated 2-year overall survival was 39% (95% confidence interval [CI], 30%-50%) for patients who received transplantation compared with 23% (95% CI, 14%-40%) for those who had received azacitidine (AZA). Using a multivariate Cox regression analysis, the benefit for HSCT was evident > 1 year after transplantation, with significantly lower overall mortality compared with those who had received AZA (hazard ratio for hematopoietic cell transplantation [HCT] vs. AZA, 0.3; P ¼ .007). The benefits of HSCT compared with non-HSCT therapies were also noted by a French group, who reported on the only prospective nonrandomized donor to no donor analysis to date.5 Patients aged 50 to 70 years who had intermediate-2 (int-2) or high-risk disease according to the International Prognosis Scoring System (IPSS) or isolated high-risk features such as a poor-risk karyotype and thrombocytopenia were enrolled prospectively. Subjects with proliferative chronic myelomonocytic leukemia and transformed MDS were also enrolled. Hypomethylating agents or induction
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Patient Selection for Allogeneic HSCT for Myelodysplastic Syndrome chemotherapy were given at the discretion of the treating physician while the donor search was ongoing. The primary comparison for the analysis was to evaluate the survival between patients with an appropriately human leukocyte antigen (HLA)-matched sibling or unrelated donor (n ¼ 112) and those without such a donor (n ¼ 50). Most (72%) of the subjects in the donor cohort had undergone transplantation at a median of 8 months after study enrollment. The survival benefit of transplantation for high-risk MDS became apparent approximately 2 years after HSCT. The 4-year survival was 37% in the donor group compared with 15% in the no donor group (P ¼ .02). The optimal method for assessing the value of HSCT is to randomize patients eligible for transplantation and perform a donor to HSCT versus no-HSCT trial. However, given that HSCT is the only potential curative option available to patients and that consensus groups have endorsed transplantation for MDS, it is unlikely that a truly randomized HSCT trial will ever be conceived. However, 2 large prospective studies are ongoing to confirm the advantages of allogeneic HSCT compared with non-HSCT approaches for MDS using biologic randomization. The Blood and Marrow Transplantation Clinical Trial Network study (BMTCTN 1102) will assess the benefits of transplantation for those patients with high-risk MDS, as defined by the IPSS, during any period of their disease course (ClinicalTrials.gov Identifier, NCT02016781).3 Patients referred for HSCT will be biologically assigned to transplant versus non-HSCT therapy according to the availability of a suitably HLA-matched sibling or unrelated donor. Patients aged 50 to 75 will be eligible for the trial, which is anticipated to enroll a minimum of 338 subjects according to donor availability. The primary study endpoint will be overall survival at 3 years after enrollment. The study will also address the patient quality of life and a cost-effectiveness analysis. The German MDS study group will evaluate, in a prospective trial, patients aged 55 to 70 years with high-risk MDS defined by IPSS and compare the outcomes of HSCT and no-HSCT, also based on donor availability (ClinicalTrials.gov identifier, NCT01404741).4 All subjects will receive 4 to 6 cycles of AZA and subsequently will be biologically assigned to transplantation on the basis of donor availability, with either an HLA-matched sibling or unrelated donor. Patients without a suitable donor will continue with AZA treatment for their MDS. The trial will assess comorbidities at study entry and before transplantation. The primary study objective will be to compare the 3-year overall survival between the 2 arms.
Usage of Prognostic Models
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Several prognostic systems have been developed to better predict MDS outcomes, including leukemic transformation and survival. The IPSS was first published in 1997 to predict MDS prognosis, including the time from diagnosis to progression to acute myelogenous leukemia (AML) or death. This model incorporates the blast percentage, presence of cytopenias, and cytogenetic risk category to stratify the disease into low, intermediate-1 (int-1), int-2, and highrisk categories at diagnosis. For patients with int-2 and high-risk disease, the average time to leukemic transformation was 1.1 and 0.2 years, and the average time to death was 1.2 years and 0.4 year, respectively.6 The IPSS has been the most widely adopted tool in clinical practice for the management of MDS, and the goals of
Clinical Lymphoma, Myeloma & Leukemia August 2016
treatment for those patients with int-2 or high-risk disease have included disease-modifying strategies that can improve survival, such as HSCT. Since then, several models were developed to predict MDS outcomes and further refine the IPSS schema. The World Health Organization Prognosis Scoring System (WPSS) incorporates the World Health Organization category and transfusion requirements and cytogenetic risk.7 Another multinational collaborative effort, known as the International Working Group for the Prognosis of MDS (IWG-PM) project, has revised the IPSS (IPSS-R) to further refine its prognostic value.8 The model classified 7012 patients into 5 risk groups (very low, low, intermediate, high, and very high risk) compared with the 4 groups in the IPSS and WPSS. The new classification incorporates the depth of cytopenias with the hemoglobin level, platelet counts, and neutrophil count cutoffs. In contrast, the previous model incorporated simply the presence or absence of cytopenias. The percentage of marrow blasts has also been further divided into 3 groups. The increase in cytogenetic categories for conventional karyotyping underscores the importance of genetic abnormalities in MDS. The newer classification notes 16 cytogenetic abnormalities compared with the previous 6 recognized in the IPSS, which are now classified within 5 risk categories. The median survival in the absence of therapy for the high- and very-high-risk categories was 1.6 years and 0.8 year, with a corresponding time to leukemic transformation in these groups of 1.4 years and 0.7 year. Several retrospective studies have highlighted the validity of the IPSS-R. In a single institution database analysis of 1088 patients, the median overall survival according to the IPSS-R risk categories was 90 months for the very-low-, 54 months for the low-, 34 months for the intermediate-, 21 months for the high-, and 13 months for the very-high-risk groups (P < .005).9 Additionally, this analysis demonstrated the survival benefit of using diseasemodifying agents such as AZA and HSCT in patients with higher risk MDS according to the IPSS-R. Patients in the high and very high IPSS-R risk groups who received AZA experienced significant improvement in survival compared with those patients who had not received AZA (median survival, 25 vs. 18 months for high risk, P < .028; and median survival, 15 vs. 9 months for very high risk, P ¼ .005). Similarly, patients with lower risk MDS by IPSS-R did not show a survival benefit from HSCT, although the use of HSCT approached statistical significance for 42 intermediate-risk patients (P ¼ .08). The benefits of HSCT were observed for patients with high- and very-high-risk disease, with significantly longer survival compared with the no-HSCT group (median survival, 40 vs. 19 months, P < .005 for high risk; median survival, 31 vs. 12 months, P < .005 for very high risk). To further identify the factors predictive for the outcomes of those patients who receive HSCT, Della Porta et al10 evaluated the survival and relapse in 519 patients with MDS or oligoblastic AML (< 30% marrow blasts) who had undergone allogeneic transplantation. On multivariate analysis, the IPSS-R risk group significantly affected survival (hazard ratio [HR], 1.41; P < .001) and relapse (HR, 1.81; P < .001). The study used the Akaike criterion to demonstrate that the IPSS-R is more indicative of prognosis than the IPSS. Compared with the IPSS-based prognostic stratification, the IPSS-R risk group changed for 65% of patients, with most patients reclassified into higher risk categories with a less favorable
Asmita Mishra, Claudio Anasetti prognosis. The improved prognostic value of the IPSS-R has also been demonstrated in a multicenter review compared with the IPSS, WPSS, and Duesseldolf score.11 Given the predictive value of the IPSS-R, the model has subsequently been incorporated into some treatment guidelines for clinical practice.12 However, the current decision algorithms regarding recommendation for transplantation are still based on the IPSS and WPSS. The first Markov model-based decision analysis to address the optimal timing for patients with MDS proceeding to HSCT using myeloablative conditioning was published > 1 decade ago.13 Using the IPSS, this model found that early transplantation improved survival for patients with int-2 or high-risk MDS but not for patients with low- or int-1erisk disease. Alessandrino et al7 similarly found that patients risk stratified by the WPSS to higher risk disease had improvement in overall outcomes with HSCT compared with best supportive care. The IPSS-R has already been used to ascertain whether HSCT is preferable to no-HSCT for individual patients. A recent decision analysis using 2 institutional cohorts has demonstrated improved survival for intermediate-risk or higher IPSS-R risk categories with early transplantation.14
However, recent analyses have suggested that somatic mutations have prognostic significance in this setting and might also predict for poor outcomes in patients receiving allogeneic HSCT. Bejar et al18 recently presented the results of next-generation sequencing in 87 patients with MDS before transplantation. Mutations were identified in most of the cohort (92%), with ASXL1 (29%), TP53 (21%), DNMT3A (18%), and RUNX1 (16%) the most commonly mutated genes. On multivariate analysis, adjusting for known prognostic variables such as complex karyotype, TP53 (HR, 4.22; P .001) and TET2 (HR, 1.68; P ¼ .037) were associated with decreased survival18; 64% of the deaths were associated with a mutation in TP53, DNMT3, or TET2. The 3-year survival was 19% (95% CI, 9%-33%) for patients with these mutations compared with 59% (95% CI, 43%-72%) for patients without these mutations.18 These findings suggest the importance of mutational analysis in patients receiving immune modulating therapy with HSCT and merit further validation in larger data sets to identify high-risk populations who might require integration of novel therapies for improved outcomes.
Role of Molecular Mutations in Patient Evaluation
Tolerability Assessment of HSCT
Mutated genes are associated with both MDS clinical phenotype and prognosis. Currently, no known disease-defining molecular mechanisms are available; however, a wide number of molecular abnormalities have been associated with cytopenias and dysplasia, contributing to understanding the heterogeneity of the disease. More than 40 somatic genetic mutations have been noted in MDS, with > 90% of patients having 1 mutation identified.15-17 It is likely that mutations in MDS-associated genes indicate clonal hematopoiesis and are associated with clinical outcomes. These genes can be broadly categorized into 4 groups: (1) splicing factors (SF3B1, SRSF2, U2AF1, ZRSR2); (2) transcription factors (RUNX1, GATA2, ETV6, TP53); (3) epigenetic regulators (TET2, DNMT3A, EZH2, IDH1/IDH2, ASXL1); and (4) growth signaling factors (NRAS, CBL, JAK2, SETBP1). Some of these mutations are associated with the clinical features and poor clinical outcomes, independent of the prognostic risk models currently in use. Mutations in TP53, EZH2, ETV6, RUNX1, and ASXL1 are predictors of poor overall survival in patients with MDS using a multivariate model adjusted for IPSS and IPSS-R.15-17 Furthermore, the presence of 1 of the prognostic mutations stratifies the patients’ risk such that their survival risk resembles the next highest IPSS group, rather than the IPSS group based solely on bone marrow blasts, cytopenias, and karyoptype.15 Haferlach et al17 evaluated the effect of molecular markers on the clinical outcomes in 875 patients. When stratified by IPSS-R, the presence of 1 of the 5 known mutations associated with worse survival in MDS was also associated with decreased survival for patients in the low- and intermediate-risk groups.17 These analyses suggest improvement of MDS risk stratification with the use of somatic mutations. The incorporation of somatic mutations into meaningful clinical decision algorithms for MDS continues to be an area of active investigation. The prognostic and predictive value of somatic mutations in patients with MDS undergoing HSCT is largely unknown.
Transplant candidate selection is not only based on patient’s diagnosis, risk, and disease burden, but also entails a detailed patient evaluation in an effort to determine patient tolerability of the procedure. This is particularly the case for patients with MDS, because this is a disease seen predominantly in the elderly who could have comorbid conditions that impair their functionality. The transplantation physician’s attitude toward patient tolerance of HSCT procedure is influenced by the assessment of chronologic age, comorbidity burden, and performance status.19 McClune et al20 reported no effect of age on HSCT in either AML or MDS using registry data from the Center for International Blood and Marrow Transplant Research. Approximately one third of patients with MDS were 60 years old. Age was not associated with survival, relapse, or nonrelapse mortality at 2 years after allografting.20 This suggests that chronologic age is not a precise predictor of transplant tolerability, and additional tools are needed to evaluate patients before treatment. A comorbidity index has been reported and recently validated to evaluate and score pretransplant comorbidities and predict nonrelapse mortality.21,22 Using an institutional database, Sorror et al21 developed a comorbidity scoring index to predict post-HSCT mortality that was published originally in 2005 (HCT-CI). This index has been validated in many settings and, more recently, in a prospectively observed cohort of > 8000 allogeneic HSCT recipients. An increased risk index was independently associated with nonrelapse mortality and survival in allogeneic HSCT recipients (P < .001 for both endpoints). Those patients with high HCT-CI scores ( 3) have a greater risk of poor outcomes, regardless of the diagnosis or patient age, underscoring the importance of the comorbidity assessment as an independent factor.22 The association of comorbidities and mortality was also evaluated in a single-institution cohort of 600 patients with MDS.23 Using a validated comorbidity scale for adults, only a small fraction of the population had no comorbid conditions (23%), with most patients having evidence of clinically significant comorbid conditions. The
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Patient Selection for Allogeneic HSCT for Myelodysplastic Syndrome median survival was 31.8, 16.8, 15.2, and 9.7 months for those with none, mild, moderate, and severe comorbidities, respectively (P < .001). These data have demonstrated the importance of the comorbidity assessment in the MDS population before HSCT.23 The separation of “functional” age versus known chronologic age is challenging.24,25 Additional functional assessment could help evaluate the health status and thus the patient’s transplant tolerability. The performance status will negatively affect survival after HSCT.20 Broderick et al26 noted variability and potential bias in physician-reported performance status in patients with cancer, with individuals > 65 years assigned lower performance status scores than patients aged < 65 years (P ¼ .04). Objectively measured physical activity levels was not predicted by chronologic age in their cohort.26 Additionally, the evaluation of performance status separately from a comorbidity evaluation is warranted because these 2 measures likely assess different aspects of a patient’s medical health status. In an analysis of > 400 adult patients who had undergone HSCT at a single institution, a weak correlation between the HCTCI scores and Karnofsky performance status (r ¼ 0.18; P ¼ .001) Furthermore, performance status did not correlate with age (r ¼ < 0.01, P ¼ .99).25 The limitations of the currently used performance status measures and comorbidity indexes have led to the evaluation and analysis of alternative supplemental tools in the hope of better ascertaining patients’ functional status pretransplantation. These studies have mainly focused on the geriatric populations and, thus, are likely to be valuable in the evaluation of patients with MDS.27,28 Functionality assessments are beginning to be investigated, including the evaluation of measurements of physical functioning before HSCT. In a recent presentation at the American Society of Clinical Oncology 2015 Annual Meeting, allogeneic HSCT recipients with self-reported vigorous activity had lower mortality than those who reported low physical activity (HR, 0.189; 95% CI, 0.063-0.567; P ¼ .003) on multivariate analysis adjusted for disease risk and Karnofsky performance status.29 Given the challenges to recovery after HSCT and the increased medical risk, additional novel methods to ascertain HSCT tolerability warrant further study.
Conclusion Allogeneic HSCT is the only curative therapy for high-risk MDS. Improved prognostic scoring systems could help identify those patients at risk of poor outcomes who are in most need of transplantation. With the additional information on somatic mutations, we will likely be able to more precisely predict the outcomes of patients treated with or without transplantation and more precisely define the transplant indications. As the proportion of transplants for MDS increases because of improvements in supportive care measures, comprehensive evaluations of patient tolerability are needed to risk stratify patients who can gain maximum benefit from HSCT.
References 1. Cazzola M, Della Porta MG, Malcovati L. The genetic basis of myelodysplasia and its clinical relevance. Blood 2013; 122:4021-34. 2. Unrelated HCT by Patient Diagnosis, Malignant Diseases: Center for International Blood and Marrow Transplant Research [cited 2015 November]. Available at: https://bethematchclinical.org/Transplant-Indications-and-Outcomes/DiseaseSpecific-Indications-and-Outcomes/MDS/. Accessed: December 15, 2015.
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3. Pasquini M, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: 2014 CIBMTR summary slides. 2015 [cited 2015 November]. Available at: http://www.cibmtr.org/ReferenceCenter/SlidesReports/SummarySlides/ Documents/2014_Summary_Slides.pptx. Accessed: December 15, 2015. 4. Platzbecker U, Schetelig J, Finke J, et al. Allogeneic hematopoietic cell transplantation in patients age 60-70 years with de novo high-risk myelodysplastic syndrome or secondary acute myelogenous leukemia: comparison with patients lacking donors who received azacitidine. Biol Blood Marrow Transplant 2012; 18: 1415-21. 5. Robin M, Porcher R, Ades L, et al. HLA-matched allogeneic stem cell transplantation improves outcome of higher risk myelodysplastic syndrome: a prospective study on behalf of SFGM-TC and GFM. Leukemia 2015; 29: 1496-501. 6. Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89:2079-88. 7. Alessandrino EP, Porta MG, Malcovati L, et al. Optimal timing of allogeneic hematopoietic stem cell transplantation in patients with myelodysplastic syndrome. Am J Hematol 2013; 88:581-8. 8. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012; 120:2454-65. 9. Mishra A, Corrales-Yepez M, Ali NA, et al. Validation of the revised International Prognostic Scoring System in treated patients with myelodysplastic syndromes. Am J Hematol 2013; 88:566-70. 10. Della Porta MG, Alessandrino EP, Bacigalupo A, et al. Predictive factors for the outcome of allogeneic transplantation in patients with MDS stratified according to the revised IPSS-R. Blood 2014; 123:2333-42. 11. Neukirchen J, Lauseker M, Blum S, et al. Validation of the revised international prognostic scoring system (IPSS-R) in patients with myelodysplastic syndrome: a multicenter study. Leuk Res 2014; 38:57-64. 12. Greenberg PL, Stone RM, Bejar R, et al. Myelodysplastic syndromes, version 2. 2015. J Natl Compr Cancer Netw 2015; 13:261-72. 13. Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 2004; 104: 579-85. 14. Della Porta MG, Alessandrino EP, Jackson CH, et al. Decision analysis of allogeneic stem cell transplantation in patients with myelodysplastic syndrome stratified according to the revised international prognostic scoring system (IPSS-R). Blood 2014; 124:531. 15. Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 2011; 364:2496-506. 16. Papaemmanuil E, Gerstung M, Malcovati L, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 2013; 122: 3616-27. 17. Haferlach T, Nagata Y, Grossmann V, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 2014; 28:241-7. 18. Bejar R, Stevenson KE, Caughey B, et al. Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation. J Clin Oncol 2014; 32:2691-8. 19. Artz AS. From biology to clinical practice: aging and hematopoietic cell transplantation. Biol Blood Marrow Transplant 2012; 18(1 suppl):S40-5. 20. McClune BL, Weisdorf DJ, Pedersen TL, et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol 2010; 28:1878-87. 21. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005; 106:2912-9. 22. Sorror ML, Logan BR, Zhu X, et al. Prospective validation of the predictive power of the hematopoietic cell transplantation comorbidity index: a Center for International Blood and Marrow Transplant Research study. Biol Blood Marrow Transplant 2015; 21:1479-87. 23. Naqvi K, Garcia-Manero G, Sardesai S, et al. Association of comorbidities with overall survival in myelodysplastic syndrome: development of a prognostic model. J Clin Oncol 2011; 29:2240-6. 24. Goldberg SL, Klumpp TR, Magdalinski AJ, Mangan KF. Value of the pretransplant evaluation in predicting toxic day-100 mortality among blood stem-cell and bone marrow transplant recipients. J Clin Oncol 1998; 16:3796-802. 25. Sorror M, Storer B, Sandmaier BM, et al. Hematopoietic cell transplantationcomorbidity index and Karnofsky performance status are independent predictors of morbidity and mortality after allogeneic nonmyeloablative hematopoietic cell transplantation. Cancer 2008; 112:1992-2001. 26. Broderick JM, Hussey J, Kennedy MJ, O’Donnell DM. Patients over 65 years are assigned lower ECOG PS scores than younger patients, although objectively measured physical activity is no different. J Geriatr Oncol 2014; 5:49-56. 27. Swanson K, van Besien K, Extermann M, et al. Geriatric assessment (GA) may identify vulnerable older allogeneic hematopoietic cell transplantation (HCT) recipients. Biol Blood Marrow Transplant 2009; 15:102-3. 28. Muffly LS, Boulukos M, Swanson K, et al. Pilot study of comprehensive geriatric assessment (CGA) in allogeneic transplant: CGA captures a high prevalence of vulnerabilities in older transplant recipients. Biol Blood Marrow Transplant 2013; 19:429-34. 29. Mishra A, Yue B, Kim J, et al. Physical activity as a predictor of outcomes in hematopoietic stem cell transplantation (HSCT) recipients, ASCO Meeting Abstracts. J Clin Oncol 2015; 33(15 suppl), abstract 7027.
Selection of Patients With Myelodysplastic Syndrome for Allogeneic Hematopoietic Stem Cell Transplantation Asmita Mishra, Claudio Anasetti Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for patients with myelodysplastic syndrome (MDS). Because MDS predominantly affects an older population, age-associated comorbidities can preclude patients from cure. HSCT is associated with the risk of morbidity and mortality; however, with safer conditioning regimens and improved supportive care, eligible patients with an appropriately matched donor can receive this therapy without exclusion by older age alone. We discuss the role of improved MDS prognostic scoring systems and molecular testing for selection for HSCT, and review the pre-HSCT tolerability assessment required for this advanced aged population. Clinical Lymphoma, Myeloma & Leukemia, Vol. 16, No. S1, S49-52 ª 2016 Elsevier Inc. All rights reserved. Keywords: HSCT, MDS, Myelodysplasia, Somatic mutations, Transplant Tolerability
Introduction Myelodysplastic syndrome (MDS) encompasses a heterogeneous spectrum of malignancies characterized by ineffective hematopoiesis and morphologic dysplasia, with a predisposition toward leukemic transformation.1 Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative therapy currently available for MDS. MDS predominantly affects older persons; thus, until recently, many patients were precluded from this curative treatment option because of age alone. However, with the development of safer transplant conditioning regimens and supportive care measures, transplantation can now be offered to a wider patient population. Thus, the HSCT volumes for MDS have increased by 3.7-fold during the past decade in the United States, and MDS is currently the second most common indication for transplantation.2,3 Comprehensive patient evaluation for transplant tolerability remains an area of active investigation, given the potential for treatment-related complications to offset the benefits of transplantation. Furthermore, with the advent of newer models with improved prognostic capacity, the indications for transplantation need to be refined and updated. Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center, Tampa, FL Submitted: Feb 9, 2016; Accepted: Feb 9, 2016 Address for correspondence: Asmita Mishra, MD, Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612 E-mail contact: asmita.mishra@moffitt.org
2152-2650/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2016.02.023
Transplantation for MDS: Comparison With Non-HSCT Therapy For patients with advanced MDS who are eligible for transplantation, the superiority of HSCT compared with non-HSCT therapies has been reported in both retrospective and prospective analyses. Platzbecker et al4 compared DNA-hypomethylating therapy (n ¼ 75) to allogeneic HSCT (n ¼ 103), using a donor versus no donor retrospective analysis of patients with MDS aged 60 to 70 years. Those patients who did not have a search for a donor because of age 60 years or those with an unsuccessful donor search were used as the control arm. The estimated 2-year overall survival was 39% (95% confidence interval [CI], 30%-50%) for patients who received transplantation compared with 23% (95% CI, 14%-40%) for those who had received azacitidine (AZA). Using a multivariate Cox regression analysis, the benefit for HSCT was evident > 1 year after transplantation, with significantly lower overall mortality compared with those who had received AZA (hazard ratio for hematopoietic cell transplantation [HCT] vs. AZA, 0.3; P ¼ .007). The benefits of HSCT compared with non-HSCT therapies were also noted by a French group, who reported on the only prospective nonrandomized donor to no donor analysis to date.5 Patients aged 50 to 70 years who had intermediate-2 (int-2) or high-risk disease according to the International Prognosis Scoring System (IPSS) or isolated high-risk features such as a poor-risk karyotype and thrombocytopenia were enrolled prospectively. Subjects with proliferative chronic myelomonocytic leukemia and transformed MDS were also enrolled. Hypomethylating agents or induction
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Patient Selection for Allogeneic HSCT for Myelodysplastic Syndrome chemotherapy were given at the discretion of the treating physician while the donor search was ongoing. The primary comparison for the analysis was to evaluate the survival between patients with an appropriately human leukocyte antigen (HLA)-matched sibling or unrelated donor (n ¼ 112) and those without such a donor (n ¼ 50). Most (72%) of the subjects in the donor cohort had undergone transplantation at a median of 8 months after study enrollment. The survival benefit of transplantation for high-risk MDS became apparent approximately 2 years after HSCT. The 4-year survival was 37% in the donor group compared with 15% in the no donor group (P ¼ .02). The optimal method for assessing the value of HSCT is to randomize patients eligible for transplantation and perform a donor to HSCT versus no-HSCT trial. However, given that HSCT is the only potential curative option available to patients and that consensus groups have endorsed transplantation for MDS, it is unlikely that a truly randomized HSCT trial will ever be conceived. However, 2 large prospective studies are ongoing to confirm the advantages of allogeneic HSCT compared with non-HSCT approaches for MDS using biologic randomization. The Blood and Marrow Transplantation Clinical Trial Network study (BMTCTN 1102) will assess the benefits of transplantation for those patients with high-risk MDS, as defined by the IPSS, during any period of their disease course (ClinicalTrials.gov Identifier, NCT02016781).3 Patients referred for HSCT will be biologically assigned to transplant versus non-HSCT therapy according to the availability of a suitably HLA-matched sibling or unrelated donor. Patients aged 50 to 75 will be eligible for the trial, which is anticipated to enroll a minimum of 338 subjects according to donor availability. The primary study endpoint will be overall survival at 3 years after enrollment. The study will also address the patient quality of life and a cost-effectiveness analysis. The German MDS study group will evaluate, in a prospective trial, patients aged 55 to 70 years with high-risk MDS defined by IPSS and compare the outcomes of HSCT and no-HSCT, also based on donor availability (ClinicalTrials.gov identifier, NCT01404741).4 All subjects will receive 4 to 6 cycles of AZA and subsequently will be biologically assigned to transplantation on the basis of donor availability, with either an HLA-matched sibling or unrelated donor. Patients without a suitable donor will continue with AZA treatment for their MDS. The trial will assess comorbidities at study entry and before transplantation. The primary study objective will be to compare the 3-year overall survival between the 2 arms.
Usage of Prognostic Models
S50
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Several prognostic systems have been developed to better predict MDS outcomes, including leukemic transformation and survival. The IPSS was first published in 1997 to predict MDS prognosis, including the time from diagnosis to progression to acute myelogenous leukemia (AML) or death. This model incorporates the blast percentage, presence of cytopenias, and cytogenetic risk category to stratify the disease into low, intermediate-1 (int-1), int-2, and highrisk categories at diagnosis. For patients with int-2 and high-risk disease, the average time to leukemic transformation was 1.1 and 0.2 years, and the average time to death was 1.2 years and 0.4 year, respectively.6 The IPSS has been the most widely adopted tool in clinical practice for the management of MDS, and the goals of
Clinical Lymphoma, Myeloma & Leukemia August 2016
treatment for those patients with int-2 or high-risk disease have included disease-modifying strategies that can improve survival, such as HSCT. Since then, several models were developed to predict MDS outcomes and further refine the IPSS schema. The World Health Organization Prognosis Scoring System (WPSS) incorporates the World Health Organization category and transfusion requirements and cytogenetic risk.7 Another multinational collaborative effort, known as the International Working Group for the Prognosis of MDS (IWG-PM) project, has revised the IPSS (IPSS-R) to further refine its prognostic value.8 The model classified 7012 patients into 5 risk groups (very low, low, intermediate, high, and very high risk) compared with the 4 groups in the IPSS and WPSS. The new classification incorporates the depth of cytopenias with the hemoglobin level, platelet counts, and neutrophil count cutoffs. In contrast, the previous model incorporated simply the presence or absence of cytopenias. The percentage of marrow blasts has also been further divided into 3 groups. The increase in cytogenetic categories for conventional karyotyping underscores the importance of genetic abnormalities in MDS. The newer classification notes 16 cytogenetic abnormalities compared with the previous 6 recognized in the IPSS, which are now classified within 5 risk categories. The median survival in the absence of therapy for the high- and very-high-risk categories was 1.6 years and 0.8 year, with a corresponding time to leukemic transformation in these groups of 1.4 years and 0.7 year. Several retrospective studies have highlighted the validity of the IPSS-R. In a single institution database analysis of 1088 patients, the median overall survival according to the IPSS-R risk categories was 90 months for the very-low-, 54 months for the low-, 34 months for the intermediate-, 21 months for the high-, and 13 months for the very-high-risk groups (P < .005).9 Additionally, this analysis demonstrated the survival benefit of using diseasemodifying agents such as AZA and HSCT in patients with higher risk MDS according to the IPSS-R. Patients in the high and very high IPSS-R risk groups who received AZA experienced significant improvement in survival compared with those patients who had not received AZA (median survival, 25 vs. 18 months for high risk, P < .028; and median survival, 15 vs. 9 months for very high risk, P ¼ .005). Similarly, patients with lower risk MDS by IPSS-R did not show a survival benefit from HSCT, although the use of HSCT approached statistical significance for 42 intermediate-risk patients (P ¼ .08). The benefits of HSCT were observed for patients with high- and very-high-risk disease, with significantly longer survival compared with the no-HSCT group (median survival, 40 vs. 19 months, P < .005 for high risk; median survival, 31 vs. 12 months, P < .005 for very high risk). To further identify the factors predictive for the outcomes of those patients who receive HSCT, Della Porta et al10 evaluated the survival and relapse in 519 patients with MDS or oligoblastic AML (< 30% marrow blasts) who had undergone allogeneic transplantation. On multivariate analysis, the IPSS-R risk group significantly affected survival (hazard ratio [HR], 1.41; P < .001) and relapse (HR, 1.81; P < .001). The study used the Akaike criterion to demonstrate that the IPSS-R is more indicative of prognosis than the IPSS. Compared with the IPSS-based prognostic stratification, the IPSS-R risk group changed for 65% of patients, with most patients reclassified into higher risk categories with a less favorable
Asmita Mishra, Claudio Anasetti prognosis. The improved prognostic value of the IPSS-R has also been demonstrated in a multicenter review compared with the IPSS, WPSS, and Duesseldolf score.11 Given the predictive value of the IPSS-R, the model has subsequently been incorporated into some treatment guidelines for clinical practice.12 However, the current decision algorithms regarding recommendation for transplantation are still based on the IPSS and WPSS. The first Markov model-based decision analysis to address the optimal timing for patients with MDS proceeding to HSCT using myeloablative conditioning was published > 1 decade ago.13 Using the IPSS, this model found that early transplantation improved survival for patients with int-2 or high-risk MDS but not for patients with low- or int-1erisk disease. Alessandrino et al7 similarly found that patients risk stratified by the WPSS to higher risk disease had improvement in overall outcomes with HSCT compared with best supportive care. The IPSS-R has already been used to ascertain whether HSCT is preferable to no-HSCT for individual patients. A recent decision analysis using 2 institutional cohorts has demonstrated improved survival for intermediate-risk or higher IPSS-R risk categories with early transplantation.14
However, recent analyses have suggested that somatic mutations have prognostic significance in this setting and might also predict for poor outcomes in patients receiving allogeneic HSCT. Bejar et al18 recently presented the results of next-generation sequencing in 87 patients with MDS before transplantation. Mutations were identified in most of the cohort (92%), with ASXL1 (29%), TP53 (21%), DNMT3A (18%), and RUNX1 (16%) the most commonly mutated genes. On multivariate analysis, adjusting for known prognostic variables such as complex karyotype, TP53 (HR, 4.22; P .001) and TET2 (HR, 1.68; P ¼ .037) were associated with decreased survival18; 64% of the deaths were associated with a mutation in TP53, DNMT3, or TET2. The 3-year survival was 19% (95% CI, 9%-33%) for patients with these mutations compared with 59% (95% CI, 43%-72%) for patients without these mutations.18 These findings suggest the importance of mutational analysis in patients receiving immune modulating therapy with HSCT and merit further validation in larger data sets to identify high-risk populations who might require integration of novel therapies for improved outcomes.
Role of Molecular Mutations in Patient Evaluation
Tolerability Assessment of HSCT
Mutated genes are associated with both MDS clinical phenotype and prognosis. Currently, no known disease-defining molecular mechanisms are available; however, a wide number of molecular abnormalities have been associated with cytopenias and dysplasia, contributing to understanding the heterogeneity of the disease. More than 40 somatic genetic mutations have been noted in MDS, with > 90% of patients having 1 mutation identified.15-17 It is likely that mutations in MDS-associated genes indicate clonal hematopoiesis and are associated with clinical outcomes. These genes can be broadly categorized into 4 groups: (1) splicing factors (SF3B1, SRSF2, U2AF1, ZRSR2); (2) transcription factors (RUNX1, GATA2, ETV6, TP53); (3) epigenetic regulators (TET2, DNMT3A, EZH2, IDH1/IDH2, ASXL1); and (4) growth signaling factors (NRAS, CBL, JAK2, SETBP1). Some of these mutations are associated with the clinical features and poor clinical outcomes, independent of the prognostic risk models currently in use. Mutations in TP53, EZH2, ETV6, RUNX1, and ASXL1 are predictors of poor overall survival in patients with MDS using a multivariate model adjusted for IPSS and IPSS-R.15-17 Furthermore, the presence of 1 of the prognostic mutations stratifies the patients’ risk such that their survival risk resembles the next highest IPSS group, rather than the IPSS group based solely on bone marrow blasts, cytopenias, and karyoptype.15 Haferlach et al17 evaluated the effect of molecular markers on the clinical outcomes in 875 patients. When stratified by IPSS-R, the presence of 1 of the 5 known mutations associated with worse survival in MDS was also associated with decreased survival for patients in the low- and intermediate-risk groups.17 These analyses suggest improvement of MDS risk stratification with the use of somatic mutations. The incorporation of somatic mutations into meaningful clinical decision algorithms for MDS continues to be an area of active investigation. The prognostic and predictive value of somatic mutations in patients with MDS undergoing HSCT is largely unknown.
Transplant candidate selection is not only based on patient’s diagnosis, risk, and disease burden, but also entails a detailed patient evaluation in an effort to determine patient tolerability of the procedure. This is particularly the case for patients with MDS, because this is a disease seen predominantly in the elderly who could have comorbid conditions that impair their functionality. The transplantation physician’s attitude toward patient tolerance of HSCT procedure is influenced by the assessment of chronologic age, comorbidity burden, and performance status.19 McClune et al20 reported no effect of age on HSCT in either AML or MDS using registry data from the Center for International Blood and Marrow Transplant Research. Approximately one third of patients with MDS were 60 years old. Age was not associated with survival, relapse, or nonrelapse mortality at 2 years after allografting.20 This suggests that chronologic age is not a precise predictor of transplant tolerability, and additional tools are needed to evaluate patients before treatment. A comorbidity index has been reported and recently validated to evaluate and score pretransplant comorbidities and predict nonrelapse mortality.21,22 Using an institutional database, Sorror et al21 developed a comorbidity scoring index to predict post-HSCT mortality that was published originally in 2005 (HCT-CI). This index has been validated in many settings and, more recently, in a prospectively observed cohort of > 8000 allogeneic HSCT recipients. An increased risk index was independently associated with nonrelapse mortality and survival in allogeneic HSCT recipients (P < .001 for both endpoints). Those patients with high HCT-CI scores ( 3) have a greater risk of poor outcomes, regardless of the diagnosis or patient age, underscoring the importance of the comorbidity assessment as an independent factor.22 The association of comorbidities and mortality was also evaluated in a single-institution cohort of 600 patients with MDS.23 Using a validated comorbidity scale for adults, only a small fraction of the population had no comorbid conditions (23%), with most patients having evidence of clinically significant comorbid conditions. The
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Patient Selection for Allogeneic HSCT for Myelodysplastic Syndrome median survival was 31.8, 16.8, 15.2, and 9.7 months for those with none, mild, moderate, and severe comorbidities, respectively (P < .001). These data have demonstrated the importance of the comorbidity assessment in the MDS population before HSCT.23 The separation of “functional” age versus known chronologic age is challenging.24,25 Additional functional assessment could help evaluate the health status and thus the patient’s transplant tolerability. The performance status will negatively affect survival after HSCT.20 Broderick et al26 noted variability and potential bias in physician-reported performance status in patients with cancer, with individuals > 65 years assigned lower performance status scores than patients aged < 65 years (P ¼ .04). Objectively measured physical activity levels was not predicted by chronologic age in their cohort.26 Additionally, the evaluation of performance status separately from a comorbidity evaluation is warranted because these 2 measures likely assess different aspects of a patient’s medical health status. In an analysis of > 400 adult patients who had undergone HSCT at a single institution, a weak correlation between the HCTCI scores and Karnofsky performance status (r ¼ 0.18; P ¼ .001) Furthermore, performance status did not correlate with age (r ¼ < 0.01, P ¼ .99).25 The limitations of the currently used performance status measures and comorbidity indexes have led to the evaluation and analysis of alternative supplemental tools in the hope of better ascertaining patients’ functional status pretransplantation. These studies have mainly focused on the geriatric populations and, thus, are likely to be valuable in the evaluation of patients with MDS.27,28 Functionality assessments are beginning to be investigated, including the evaluation of measurements of physical functioning before HSCT. In a recent presentation at the American Society of Clinical Oncology 2015 Annual Meeting, allogeneic HSCT recipients with self-reported vigorous activity had lower mortality than those who reported low physical activity (HR, 0.189; 95% CI, 0.063-0.567; P ¼ .003) on multivariate analysis adjusted for disease risk and Karnofsky performance status.29 Given the challenges to recovery after HSCT and the increased medical risk, additional novel methods to ascertain HSCT tolerability warrant further study.
Conclusion Allogeneic HSCT is the only curative therapy for high-risk MDS. Improved prognostic scoring systems could help identify those patients at risk of poor outcomes who are in most need of transplantation. With the additional information on somatic mutations, we will likely be able to more precisely predict the outcomes of patients treated with or without transplantation and more precisely define the transplant indications. As the proportion of transplants for MDS increases because of improvements in supportive care measures, comprehensive evaluations of patient tolerability are needed to risk stratify patients who can gain maximum benefit from HSCT.
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